Allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning is the primary cure for most patients with primary immunodeficiency and other inherited nonmalignant diseases. However, many patients who could potentially benefit from HCT are ineligible due to co-morbid conditions such as opportunistic infections and disease related organ dysfunction that place them at a prohibitively high risk of transplant related mortality (TRM) with conventional myeloablative regimens. Therefore, strategies that decrease transplant related toxicity without compromising engraftment and disease responses are needed. We treated 18 patients with nonmyeloablative regimens that either included no conditioning (n=2), 2 Gy total body irradiation (TBI;n=3), or 2 Gy TBI plus fludarabine (n=13) followed by postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. Importantly, markedly decreased TRM was observed compared to conventional regimens, and disease responses were seen in both mixed donor/host and complete donor hematopoietic chimeras. However, in a proportion of patients, low donor chimerism levels and graft versus host disease (GVHD) remained obstacles to complete success of this approach. Therefore, my overall objective is to develop more effective nonmyeloablative HCT regimens for patients with nonmalignant disorders. To accomplish this, we propose 2 steps. First, marrow will be the only source of hematopoietic stem cells in order to avoid the high incidence of chronic GVHD associated with peripheral blood mononuclear cell grafts. In addition, Campath-1 H will be added to the current nonmyeloablative regimen of 2 Gy TBI plus fludarabine, with the aim of achieving more uniform donor chimerism/engraftment and at the same time, better controlling GVHD (Specific Aim 1). Further, many patients do not have HLA- matched related or unrelated donors. Therefore, my other research efforts are focused on developing safe and effective approaches to HCT from HLA-haploidentical related donors (Specific Aim 2). Importantly, detailed immune reconstitution studies will be performed on patients enrolled on these studies (Specific Aim 3). Relevance: The overall goal of this proposal is to provide safe, effective, and more uniformly curative therapies for patients with nonmalignant disorders. Information gained from these studies will be particularly important for patients with nonmalignant disorders.